The proposed project involves the chemical synthesis of potent, specific and reversible inhibitors of thrombin. The selection of the structural features to be incorporated into the inhibitors is governed by: (a) the known structure of the fibrinopeptide A region of fibrinogen; (b) general concepts predicted by "transition-state analog inhibitors " for other enzyme catalyzed reactions; and, (c) the binding properties of other serine proteinases. The classes of inhibitors selected by these criteria include small molecule boronic acids, arsonic acids and aromatic aldehydes as well as polypeptides containing an aldehyde functionality at the C-terminus. The interaction of the inhibitors with thrombin will be studied by a variety of techniques including: steady state enzyme inhibition kinetics, fluorescence spectroscopy, dye displacement, UV difference spectroscopy and if possible HI and C 13 nuclear magnetic resonance spectrometry. The effects of these inhibitors on other components of the clotting system as well as on the kallikrein and complement systems will be screened. The proposed inhibitors may have potential utility for treatment of thromboembolic disease, inhibition of local and general inflammatory processes and control of some aspects of the pathology of the complement system. Furthermore these inhibitors may be useful as specific inhibitors of surface plasminogen activators of some neoplastic cells.